DESCRIPTION(From applicant's abstract): In his long-standing interests in determining neurobiological mechanisms of adenosine, the principal investigator has constructed a novel hypothesis that release of intracellular adenosine results not only from an increase in intracellular calcium levels but also from an acidification of intracellular milieu, as measured by an decrease in intracellular pH values. This proposal will predominately use the hippocampal slice preparation to explore various aspects of adenosine neurobiology from an electrophysiological point of view. The first aim will explore the role of intracellular pH and calcium in mediating adenosine release. These studies will explore whether changes in intracellular calcium and pH are both necessary and sufficient to produce adenosine release by using a variety of reagents which affect the intracellular milieu. The second specific aim explore whether adenosine plays an important role in regulating the basic excitability of neurons by performing experiments in adenosine A1 receptor-knockout mice. These studies will determine whether hippocampal slices from KO mice are hyperexcitable, and whether KO of adenosine A1 receptors affect the function of other inhibitory receptors.